Furosemide is a loop diuretic widely used to treat congestive heart failure (CHF) and other edematous conditions to rid the body of excess water, reduce blood pressure, and mobilize edemas. However, due to the narrow window of furosemide absorption, occurring in the proximal gastrointestinal tract, only immediate release oral formulations are clinically available. The most common pharmaceutical formulation of furosemide, LASIX®, a current diuretic for treating congestive heart failure (CHF), is absorbed only in the proximal small intestines [8]. Furosemide is a weak acid (pKa 3.9), and is protonated only in the acidic lumen of the stomach and proximal small intestines [23]. In the more distal gastrointestinal (GI) tract, furosemide becomes deprotonated and carries a negative charge that significantly reduces its ability to cross biological membranes [8]. Compounding the site specificity of absorption, furosemide has low water solubility leading to its classification as a class IV narrow absorption window therapeutic [16,26].
Accordingly, furosemide bioactivity is characterized by a sharp onset of diuresis (“the “Niagara effect”) that occurs when furosemide blocks the sodium/potassium/chlorine (Na—K-2Cl) co-transporter (NKCC) in the thick ascending limb of the kidneys causing diuresis [11]. Bolus and continuous administration of furosemide in intravenous settings in patients experiencing severe CHF demonstrate that continuous administration at lower concentrations produced greater diuretic efficiency and reduced subsequent hospitalization rates. Congestive heart failure patients who are treated with Lasix experience rapid diuresis followed by an increase in water intake over the course of the day that leads to peaks and troughs in blood pressure and leads to development of patient tolerance (i.e., a decrease in efficacy) of Lasix that requires increased dosing as a function of the time period of course of treatment [12]. Current formulations of furosemide have bioactivity profiles that are inconvenient for patients, produce inefficient diuresis, and cause increased renal stress with dose escalation. Renal stress is associated with kidney failure later in life, and development of high blood pressure. There is a need for improved formulations of loop diuretics and other hydrophobic compounds.